EP2659891A1 - Drug with activity against the herpes virus family - Google Patents
Drug with activity against the herpes virus family Download PDFInfo
- Publication number
- EP2659891A1 EP2659891A1 EP11853372.8A EP11853372A EP2659891A1 EP 2659891 A1 EP2659891 A1 EP 2659891A1 EP 11853372 A EP11853372 A EP 11853372A EP 2659891 A1 EP2659891 A1 EP 2659891A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- drug
- activity against
- tablets
- virus
- herpes virus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 241001529453 unidentified herpesvirus Species 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 230000000694 effects Effects 0.000 title claims abstract description 7
- 229940079593 drug Drugs 0.000 title claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 8
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical class NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 5
- 229940002226 buccal film Drugs 0.000 claims abstract description 4
- 239000002775 capsule Substances 0.000 claims abstract description 4
- 229940112822 chewing gum Drugs 0.000 claims abstract description 4
- 235000015218 chewing gum Nutrition 0.000 claims abstract description 4
- 239000006071 cream Substances 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 4
- 239000002674 ointment Substances 0.000 claims abstract description 4
- 238000007911 parenteral administration Methods 0.000 claims abstract description 4
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 4
- 239000007921 spray Substances 0.000 claims abstract description 4
- 239000000829 suppository Substances 0.000 claims abstract description 4
- 239000003826 tablet Substances 0.000 claims abstract description 4
- 239000006190 sub-lingual tablet Substances 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 16
- 239000000126 substance Substances 0.000 abstract description 14
- 229960004150 aciclovir Drugs 0.000 description 11
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 230000000840 anti-viral effect Effects 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 241000700605 Viruses Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 241000700584 Simplexvirus Species 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 210000003501 vero cell Anatomy 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000120 cytopathologic effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229960004396 famciclovir Drugs 0.000 description 3
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- BIYXGLPPMRDUNY-UHFFFAOYSA-N pentyl n-phenylcarbamate Chemical compound CCCCCOC(=O)NC1=CC=CC=C1 BIYXGLPPMRDUNY-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 229910003202 NH4 Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000012888 bovine serum Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002941 microtiter virus yield reduction assay Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003602 anti-herpes Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000003562 morphometric effect Effects 0.000 description 1
- 238000013425 morphometry Methods 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000004540 process dynamic Methods 0.000 description 1
- UOVLOQNKWCYEQK-UHFFFAOYSA-N propan-2-ol;tetrachloromethane Chemical compound CC(C)O.ClC(Cl)(Cl)Cl UOVLOQNKWCYEQK-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- -1 sulpho Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
Definitions
- the invention relates to medicine, and specifically to synthetic biologically active derivatives of carbopentoxysulfanilic acid.
- the inventive substance has pronounced antiviral activity, mainly against various viruses of the herpes family.
- It can be used in medicine, veterinary science and cosmetic science for preventing and treating diseases related to the herpes virus family.
- Aciclovir is less active against type II herpes viruses, famciclovir has an extensive list of contraindications, however the majority of circulating herpes viruses currently are resistant towards these preparations that have been used for a long time ( P.A.Furman, D.M.Coen, M.H.St.Clair and P.A.Schaffer Aciclovir-resistant mutants of herpes simplex virus type 1 express altered DNA polymerase or reduced aciclovir phosphorylating activities. J. Virol. 1981 December; 3: 936-941 ) (a copy of the link is attached).
- aciclovir 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purine-6-on has been taken as a prototype, (see http://www.rlsnet.ru/mnn_index_id_290.htm ) (a copy of the link is attached):
- a novel substance that is a (2,6-dichlorophenyl)amide salt of carbopentoxysulfanilic acid of general formula: where X is Na, K, NH 4 ;
- the drug may be contained in tablets, including sublingual tablets, or in capsules, or in suppositories, or in drops, or in mixtures, or in ointments, creams or other forms for application to the skin and mucosae, or in an oral-buccal film, or in a spray, or in a liquid for parenteral administration, or in chewing gum.
- the inventive drug exhibits pronounced activity against the lager part of herpes viruses.
- Synthesis of the inventive substance is performed in several stages.
- Antiviral activity of the inventive substance was determined using the model of pneumonia in white mice caused by type I herpes simplex virus.
- Herpes simplex virus of type I was accumulated in Vero cells cultured in MEM medium with the addition of 0.2% bovine serum, 50 ⁇ g/ml of gentamicin. Virus titration was performed on Vero cells cultured in 96-well plates. Results were recorded after a pronounced cytopathic effect (CPE) appeared in virus control. The degree of intactness of the cellular monolayer was assessed visually, virus titer was calculated as the reciprocal value of Briggs logarithm of the largest dilution of the source material that is still able to produce visually notable manifestations of CPE in the cell culture (CTD50).
- CPE cytopathic effect
- mice For assessing the virus inhibiting action of the preparations, white non-pedigree mice weighing 12-15 g ("Rappolovo" farm, Leningrad Region) were infected intranasally under a light ether anaesthesia with the herpes simplex virus in the dosage of 106 (CTD50)/0.05 ml.
- CCD50 herpes simplex virus
- the preparation under study was administered intragastrically in the dosage of 50 mg/kg of weight according to a medical-preventive scheme (24 h and 1 h prior to infection, and 24 h and 48 h after the animals were infected).
- the lungs of the infected animals were removed, homogenized in the presence of 10-fold volume of phosphate buffer and then 10-fold dilutions from 10-1 to 10-6 were prepared thereof.
- the lung material was also subjected to histologic examination.
- Table 2 show that the preparation has a statistically significant virus-inhibitory activity at the model of herpetic pneumonia in vivo, and surpasses aciclovir with the same dosage.
- Herpes simplex virus (strain EC) was grown in Vero cells cultured in MEM medium with the addition of 0.2% bovine serum and 50 mg/l of the preparations under study.
- the inventive substance can be contained in tablets or in capsules, or in suppositories, or in drops, or in mixtures, or in ointments, creams or other forms for application to the skin and mucosae, or in an oral-buccal film, or in a spray, or in a liquid for parenteral administration, or in chewing gum.
- the invention can be implemented by means of known materials and equipment. In applicant's opinion, this enables to conclude that the inventions conform to the criterion "Industrial Applicability" (IA).
- Table 4 Preparation Number (%) of unaltered cells Herpes virus of type I Herpes virus of type II Reference (non-infected cells) 10000 (100%) 10000 (100%) Aciclovir 7000 (65%) 7000 (70%) The inventive substance 8000 (80%) 9000 (90%)
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
- The invention relates to medicine, and specifically to synthetic biologically active derivatives of carbopentoxysulfanilic acid.
- The inventive substance has pronounced antiviral activity, mainly against various viruses of the herpes family.
- It can be used in medicine, veterinary science and cosmetic science for preventing and treating diseases related to the herpes virus family.
- One of the most serious problems of modem medicine consists in virus infections, the majority of which are extremely difficult to treat or even lack an adequate antiviral therapy. Said difficulty is due to insufficient effectiveness of existing preparations and the fast variability of causative agents that leads to emergence of resistant forms (see http://www.medinfo.ru/sovety/derm/02.phtml).
- Similar problems exist in veterinary science.
- The most popular preparations for treating wide-spread infections caused by herpes simplex virus are aciclovir, a synthetic acyclic analogue of deoxyguanosine, and Famvir (famciclovir), which transforms in the organism into an active antiviral compound penciclovir (see http://www.rlsnet.ru/ mnn_index_id_1843.htm). Each of the abovementioned preparations has certain disadvantages. Aciclovir is less active against type II herpes viruses, famciclovir has an extensive list of contraindications, however the majority of circulating herpes viruses currently are resistant towards these preparations that have been used for a long time (P.A.Furman, D.M.Coen, M.H.St.Clair and P.A.Schaffer Aciclovir-resistant mutants of herpes simplex virus type 1 express altered DNA polymerase or reduced aciclovir phosphorylating activities. J. Virol. 1981 December; 3: 936-941) (a copy of the link is attached).
-
- Its disadvantage consists in the abovementioned fact that the majority of herpes viruses have acquired resistance towards this preparation.
- It is an object of the present invention to create a preparation having pronounced activity against herpes viruses.
- According to the invention there is provided synthesis of a novel substance that is a (2,6-dichlorophenyl)amide salt of carbopentoxysulfanilic acid of general formula:
- The applicant has not found any sources of information containing data on technical solutions identical to this invention, which enables to conclude that the invention conforms to the criterion "Novelty" (N).
- The inventive drug exhibits pronounced activity against the lager part of herpes viruses.
- The applicant has not found any sources of information containing data on the influence of the features of the invention on the technical result produced by their implementation. In applicant's opinion, this enables to conclude that the present technical solution conforms to the criterion "Inventive Step" (IS).
- The invention is further explained, by way of detailed description of examples of its embodiments, without reference to any drawings.
- Synthesis of the inventive substance is performed in several stages.
- 8.5 g (0.096 mol) of amyl alcohol were added drop-wise while stirring to 11.5 g (0.096 mol) of phenylisocyanate placed into a beaker. The warming-up of the reaction mass was observed. After 1 hour the mixture solidified in the form of colorless crystals. The output of phenylcarbamic acid amyl ester amounted to approximately 100%.
- 2.07 g (0.010 mol) of phenylcarbamic acid amyl ester were slowly added while stirring to 17.5 g (0.150 mol) of chlorosulfonic acid heated to 30°C, maintaining the temperature of reaction mass not higher than 35°C. Then the mixture was slowly heated to 50°C and maintained at 50-55°C for 2 hours. The obtained sulpho mass was poured to ice while stirring, maintaining the temperature not higher than 20°C. The residue was filtered, washed with ice water until obtaining pH 7 of the filtrate. The residue was air-dried and then dried in a desiccator. Output of carbopentoxysulfanilic acid chloride amounted to approximately 100%.
- 6.2 g (0.0203 mol) of carbopentoxysulfanilic acid chloride were added portion-wise at a temperature of 85°C to a mixture of 2.2 g (0.0136 mol) of 2,6-dichloroaniline and 3.23 g (0.0406 mol) of pyridine. Then the reaction mass was stirred for 45 minutes at a temperature of 80°C. Then 20 ml of hot water were added to the mass, the mixture was acidified with hydrochloric acid until obtaining pH 3-4 and cooled down to room temperature. The obtained residue was filtered, washed with water until the odor of pyridine disappeared and then dried. After recrystallization from 80% ethanol the output of target product amounted to 2.5 g (40% of the theoretical value).
- 0.232 g of caustic soda were dissolved in 5 ml of ethyl alcohol (abs.) and 2.5 g of (2,6-dichlorophenyl)amide of carbopentoxysulfanilic acid were dissolved in 30 ml of ethyl alcohol (abs.). Then the two solutions were mixed and stirred for 20 minutes. After that the ethyl alcohol was distilled off under vacuum. The remaining residue was dried. The output of product amounted to 2.1 g (80% of the theoretical value).
- Synthesis of potassium and ammonium salts is performed in a similar way.
- Individuality of the substances was proved by means of the thin-layer chromatography method at Silufol UV-254 plates, eluent carbon tetrachloride - isopropanol = 2:1. The structure of synthesized substances was proved by means of PMR spectroscopy method.
- Antiviral activity of the inventive substance was determined using the model of pneumonia in white mice caused by type I herpes simplex virus.
- Herpes simplex virus of type I (strain EC) was accumulated in Vero cells cultured in MEM medium with the addition of 0.2% bovine serum, 50 µg/ml of gentamicin. Virus titration was performed on Vero cells cultured in 96-well plates. Results were recorded after a pronounced cytopathic effect (CPE) appeared in virus control. The degree of intactness of the cellular monolayer was assessed visually, virus titer was calculated as the reciprocal value of Briggs logarithm of the largest dilution of the source material that is still able to produce visually notable manifestations of CPE in the cell culture (CTD50).
- For assessing the virus inhibiting action of the preparations, white non-pedigree mice weighing 12-15 g ("Rappolovo" farm, Leningrad Region) were infected intranasally under a light ether anaesthesia with the herpes simplex virus in the dosage of 106 (CTD50)/0.05 ml. The preparation under study was administered intragastrically in the dosage of 50 mg/kg of weight according to a medical-preventive scheme (24 h and 1 h prior to infection, and 24 h and 48 h after the animals were infected). On day 3 the lungs of the infected animals were removed, homogenized in the presence of 10-fold volume of phosphate buffer and then 10-fold dilutions from 10-1 to 10-6 were prepared thereof. Dilutions of the lungs homogenate were used for infecting the intact culture of Vero cells and for titration of virus progeny. Positive reference was represented by lungs of mice that instead of the studied preparation received physiological solution by intragastric administration, whereas negative reference was represented by lungs of mice that received aciclovir in the dosage of 50 mg/kg of weight according to the same scheme. Each experimental group consisted of 10 animals.
- The lung material was also subjected to histologic examination.
- The data provided in Table 2 show that the preparation has a statistically significant virus-inhibitory activity at the model of herpetic pneumonia in vivo, and surpasses aciclovir with the same dosage.
- Herpes simplex virus (strain EC) was grown in Vero cells cultured in MEM medium with the addition of 0.2% bovine serum and 50 mg/l of the preparations under study.
- It has been thus determined that the antiviral activity of the inventive substance significantly exceeds that of the aciclovir, in particular against the herpes virus of type II.
- The inventive substance can be contained in tablets or in capsules, or in suppositories, or in drops, or in mixtures, or in ointments, creams or other forms for application to the skin and mucosae, or in an oral-buccal film, or in a spray, or in a liquid for parenteral administration, or in chewing gum.
- The inventive substance manifests practically identical antiviral activity with X = Na, K or NH4.
- The invention can be implemented by means of known materials and equipment. In applicant's opinion, this enables to conclude that the inventions conform to the criterion "Industrial Applicability" (IA).
- Physical and chemical characteristics of the target compounds
Table 1 X Tmelting, °C PMR spectrum, ppm NH Ar OCH2 CH3, CH2 Na (I) 120 9.75; 9.9 7.2-7.7 4.1 0.9; 1.38; 1.62 K (II) 123 9.8; 10.0 7.3-7.8 4.15 0.94; 1.42; 1.65 NH4 + (III) 110 (decomp.) *) *) 4.2 0.91; 1.40; 1.63 *) The region of PMR spectrum of ammonium salt in low field (> 7 ppm) is not characteristic: one wide signal is observed, which is caused by the formation of strong hydrogen bonds in the solution. -
Table 2 Preparation Virus titer in lungs of mice on day 3 after the infection, Lg CTD50 Reference 3.6 ± 0.15 The inventive substance 1.0 ± 0.11 Aciclovir 1.4 ± 0.34 -
Table 3 Preparation Term of experiment (in days) Number of inflammation foci in one animal Area of an inflammation focus in section Reference 2 10 76 ± 5.9 4 10 405 ± 111.3 6 10 343 ± 47.5 Aciclovir 2 8 55 ± 9.4 4 3 58 ± 14.7 6 3 24 ± 6.4 The inventive substance 2 3 47 ± 7.3 4 2 49 ± 12.1 6 1 14 ± 5.5 -
Table 4 Preparation Number (%) of unaltered cells Herpes virus of type I Herpes virus of type II Reference (non-infected cells) 10000 (100%) 10000 (100%) Aciclovir 7000 (65%) 7000 (70%) The inventive substance 8000 (80%) 9000 (90%)
Claims (2)
- A drug according to claim 1, characterized in that it is contained in tablets, including sublingual tablets, or in capsules, or in suppositories, or in drops, or in mixtures, or in ointments, creams or other forms for application to the skin and mucosae, or in an oral-buccal film, or in a spray, or in a liquid for parenteral administration, or in chewing gum.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
RU2010153852/15A RU2452490C1 (en) | 2010-12-27 | 2010-12-27 | Drug with herpes virus family activity |
PCT/RU2011/000060 WO2012091610A1 (en) | 2010-12-27 | 2011-01-28 | Drug with activity against the herpes virus family |
Publications (3)
Publication Number | Publication Date |
---|---|
EP2659891A1 true EP2659891A1 (en) | 2013-11-06 |
EP2659891A4 EP2659891A4 (en) | 2014-01-08 |
EP2659891B1 EP2659891B1 (en) | 2015-03-18 |
Family
ID=46383366
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP11853372.8A Active EP2659891B1 (en) | 2010-12-27 | 2011-01-28 | Drug with activity against the herpes virus family |
Country Status (4)
Country | Link |
---|---|
US (2) | US9567295B2 (en) |
EP (1) | EP2659891B1 (en) |
RU (1) | RU2452490C1 (en) |
WO (1) | WO2012091610A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3006020A4 (en) * | 2013-06-07 | 2017-02-15 | Viktor Veniaminovich Tets | Method for treating recurring skin and mucous membrane diseases caused by hsv-1 and hsv-2 |
US10098899B2 (en) | 2010-12-27 | 2018-10-16 | Viktor Veniaminovich Tets | Drug with activity against the herpes virus family |
EP3351530A4 (en) * | 2015-09-15 | 2019-04-10 | Viktor Veniaminovich Tets | Method of producing a sodium salt of (2,6-dichlorophenyl)amide carbopentoxysulphanilic acid |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US10098899B2 (en) | 2010-12-27 | 2018-10-16 | Viktor Veniaminovich Tets | Drug with activity against the herpes virus family |
EP3006020A4 (en) * | 2013-06-07 | 2017-02-15 | Viktor Veniaminovich Tets | Method for treating recurring skin and mucous membrane diseases caused by hsv-1 and hsv-2 |
US9757396B2 (en) | 2013-06-07 | 2017-09-12 | Viktor Veniaminovich Tets | Method for treating recurring skin and mucous membrane diseases caused by HSV-1 and HSV-2 |
US10080761B2 (en) | 2013-06-07 | 2018-09-25 | Viktor Veniaminovich Tets | Method for treating recurring skin and mucous membrane diseases caused by HSV-1 and HSV-2 |
EP3351530A4 (en) * | 2015-09-15 | 2019-04-10 | Viktor Veniaminovich Tets | Method of producing a sodium salt of (2,6-dichlorophenyl)amide carbopentoxysulphanilic acid |
US10584095B2 (en) | 2015-09-15 | 2020-03-10 | Viktor Veniaminovich Tets | Method of producing a sodium salt of (2,6-dichlorophenyl)amide carbopentoxysulfanilic acid |
Also Published As
Publication number | Publication date |
---|---|
WO2012091610A1 (en) | 2012-07-05 |
RU2452490C1 (en) | 2012-06-10 |
US9567295B2 (en) | 2017-02-14 |
US10098899B2 (en) | 2018-10-16 |
EP2659891A4 (en) | 2014-01-08 |
US20170232010A1 (en) | 2017-08-17 |
US20130287841A1 (en) | 2013-10-31 |
EP2659891B1 (en) | 2015-03-18 |
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